This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The mitochondrial encephalomyopathy, lactic acidosis, with stroke-like episodes (MELAS) syndrome is one of the most frequent maternally inherited mitochondrial disorders. It has a broad spectrum of symptoms and variable age of onset. Common manifestations include exercise intolerance, stroke-like episodes, epilepsy, ragged red fibers, lactic acidosis, and dementia. It has been estimated that one third of individuals with MELAS syndrome develop diabetes mellitus (DM). The pathogenesis of DM in MELAS syndrome is not clear and there are no clinical studies evaluating glucose/insulin metabolism in individuals with MELAS syndrome. We hypothesize that DM develops in individuals with MELAS syndrome due to multiple defects in glucose/insulin metabolism and that individuals with MELAS syndromes who do not yet have DM have altered glucose/insulin metabolism. To investigate these hypotheses, we designed a clinical study to assess glucose/insulin metabolism in individuals with MELAS syndrome who do or do not have DM, and in healthy control individuals. Glucose/insulin metabolism will be assessed by glucose isotope infusion technique and measuring the rates of endogenous glucose production, gluconeogenesis, glycogenolysis, glucose oxidation, and glucose clearance;insulin levels;and insulin sensitivity. Understanding the pathophysiological mechanism of DM in MELAS syndrome can influence the management and prognosis of DM in subjects with MELAS syndrome, and may provide more insight of the pathogenesis of DM in mitochondrial diseases in general.